“Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder”

“Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder”

 Davis AK, Barrett FS, May DG, et al. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2021;78(5):481–489. doi:10.1001/jamapsychiatry.2020.3285


Link to journal – https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2772630





Importance –

Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression.


Objective –

To investigate the effect of psilocybin therapy in patients with MDD.


Design, Setting, and Participants –

This randomized, waiting list–controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population).


Interventions – 

Two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay.


Main Outcomes and Measures

The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR).


Results –

Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 post-session assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d = 2.5; 95% CI, 1.4-3.5; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.5-3.7; P < .001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d = 2.6; 95% CI, 1.8-3.5; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 2.3; 95% CI, 1.5-3.0; P < .001). In the overall sample, 17 participants (71%) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score).


Conclusions and Relevance

Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression.


Trial Registration –  ClinicalTrials.gov Identifier: NCT03181529




Key Points:


Eligibility Criteria and Design


  • Patients were eligible for study participation if they had been diagnosed with moderate/severe major depressive disorder episodes (in line with the structured clinical interview for DSM-5 and the GRID-Hamilton depression rating scale (score ³ 17)).


  • Aged between 21-75



  • Self-reported no current pharmacotherapy for depression



  • Participants did not take any antidepressants for a minimum of 5 half-lives prior to screening and up to 4 months post-enrollment. This ensured no conflicting drug-drug interactions rendered results invalid.



  • After screening, 27 participants were randomized to either an immediate treatment group or a delayed treatment group.



  • Delayed treatment acts as control, as it allows for a comparison between immediate effects of psilocybin treatment vs any potential spontaneous improvements. The delay period was 8 weeks in length.



  • Total intervention period (period of psilocybin treatment) was 8 weeks with a minimum of 18 in-person visits. 2 psilocybin administration sessions were scheduled, an average of 1.6 weeks apart, each including 2 session facilitators. Initial psilocybin dose was relatively high at 20mg/70kg, and slightly higher at the time of the secondary dose (30mg/70kg). Facilitators were present to respond to participants needs during the administration session.



  • Psilocybin was administered in opaque gelatin capsules and ingested with roughly 100ml water.



  • This protocol was mirrored by the delayed treatment group 8 weeks after the group undergoing immediate treatment. For participant safety, regular in-person welfare visits were made






  • Primary outcome measure was the GRID-HAMD score which was performed by a blinded researcher at baseline and at weeks 1 and 4 following second psilocybin administration session for those in the immediate treatment group and at weeks 5 and 8 for those in the delayed treatment group.



  • In the group receiving immediate psilocybin treatment, 71% of participants exhibited a clinically significant improvement of symptoms at weeks 1 and 4 post-treatment



  • 58% (week 1) and 54% (week 4) of participants met the criteria for remission of depression.



  • GRID-HAMD scores were significantly more positive in the group receiving immediate treatment (measured at weeks 1 and 4) than in the delayed treatment group (measured at weeks 5 and 8 pre-treatment).




Concluding remarks: This study exhibits the potential of moderately high-dose psilocybin treatment to exert rapid antidepressant effects in those with major depressive disorder. Further research is needed into the neurophysiological mechanisms that underpin this action, however clinical trials remain positive.


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